The objectives of this research program are to define the basic immunology of the serum IgA immune system, with particular attention to its role as an orchestrator and modulator of the overall immune response to environmentally encountered antigens and to relate this normal immunologic function to its occasional role in producing susceptibility to blood stream invasion by Gram negative bacteria. The model used will be disseminated disease due to Neisseria meningitidis. Increased levels of antigen specific serum IgA have been shown to induce susceptibility to disseminated meningococcal disease by blocking complement-mediated immune lysis, the primary effector mechanism restricting the organism to its commensal niche on the moist mucous membranes of man's upper respiratory tract. Such levels of antigen specific IgA are induced by enteric colonization by bacteria of diverse genera that elaborate surface antigens immunochemically indistinquishable from those of N. meningitidis. The molecular basis of IgA blockage will be sought by dissecting the interactions of surface antigens with Ig of the three majro isotypes, using ligand/receptor models, and their interactions with the alternative and classical complement pathways. The antigenic specificity of blocking IgA will be further identified, and the relationship of its induction to the epidemiology of meningococcal disease explored.